Realizing that viruses persist and in doing so cause disease is one of the major accomplishments in virology. The principles of how this occurs is the topic for this revised productive research grant for which funding for the 35th to 40th year is requested. Our tact is to use lymphocytic choriomeningitis virus (LCMV) infection of its natural host, the mouse, to uncover principles involved and extend them to human viruses and human diseases. The success of this approach (by ourselves and others) provided the initial findings for virus-antiviral antibody immune complexes, CD8 CTL-mediated killing, CD4 help for maintaining CD8 activity, fine mapping of T cell epitopes, MHC restriction; expansion, contraction and memory of antigen-specific CD8, CD4 and B lymphocytes, use of adoptive transfer of memory T cells to abort persistent infection and the ability of non-lyric persistent viruses to cause disease by altering differentiated function of the infected cell without affecting its viral function. Immunosurveillance is primarily the function of T cells. We have developed a novel technology that allows trafficking and quantitation of both CD8 and CD4 virus (antigen)-specific T cells in vivo, and visualization of their and non-antigen-specific T cell location in virally infected tissues. The first focus of this grant is the use of tetramers, and of GFP x antigen-specific CD8 T cells to investigate the anatomic and molecular events occurring in vivo at the site of interaction between antigen-specific T cells and virus-infected cells. Included within this focus is the study of RFP x CD4 virus (antigen)-specific T cells alone and in conjunction with GFP x antigen-specific CD8 T cells in tissues during acute and persistent infections. The second focus is on how virus subverts the generation of, recognition or activity of T cells against virally infected cells. Here we will expand our recent finding during the current grant period that LCMV variants can interfere with the antigen presentation function of dendritic cells resulting in a generalized immunosuppression by dissecting the biologic and molecular mechanism(s) involved. Lessons learned from this aspect of the LCMV model should provide insights for several persistent human viral infections that cause immunosuppression.